Sci. Aging Knowl. Environ., 11 August 2004
Mouse vaccine that neutralizes one Alzheimer's protein also eliminates another
If the sheriff knocks off Bonnie, Clyde might hightail it out of town. Similarly, getting rid of -amyloid plaques in Alzheimer's mice also clears out early-stage tau deposits, new research shows. However, late in the disease, tau switches into a form that resists this treatment. Despite the limitation, the results offer encouragement for human Alzheimer's vaccines and therapies.
Alzheimer's disease (AD) ravages the brain with two different scourges. A protein called amyloid coalesces into gunky plaques; another protein, tau, forms strings--or "tangles." Preliminary studies in humans and mice suggest that antibodies that bind amyloid also attack plaques. Last year, neuroscientist Frank LaFerla of the University of California, Irvine, and colleagues generated mice that produce defective versions of three human proteins--two that help amyloid form plaques, and tau. Mice with one copy of each marred gene had plaques and pretangle tau aggregates by 1 year of age; those with two copies develop plaques and full-blown tangles at the same age.
To understand whether antibodies to amyloid might curb Alzheimer's tau pathology, the team injected them into one side of the brains of 6-month-old and 1-year-old mice. Three days later, plaques in all animals had vanished on the injected side; the junk remained on the other. Seven days after injection, the one-copy animals had tau aggregates on the untreated side only, but the yearlings with a double dose of defective tau carried tangles in both halves. In the younger--6-month-old--double-copy brains, however, tau aggregates disappeared on the injected side. Because the older animals didn't respond to the treatment, the findings suggest that the tau aggregates turn into tangles that become resistant to the treatment over time.
Previous results hinted that phosphate groups on tau help it form tangles (see Guo Perspective). In the new work, LaFerla and colleagues showed that these adornments decorated the tau that could not be cleared by -amyloid antibodies, such as that in the 12-month-old mice with two copies of each defective gene; tau in the earlier disease stage remained free of phosphates. "Tau goes through some sort of change that can't be reversed," says neuroscientist Michael Hutton of the Mayo Clinic in Jacksonville, Florida. "That implies the existence of a critical step in the development of tau pathology."
To determine whether tangle formation depends on the presence of amyloid, the researchers injected into single-copy, year-old mice a chemical that prevents the formation of amyloid. Only the brain halves receiving this treatment lost pretangle tau aggregates in addition to losing plaques, suggesting that -amyloid antibodies torpedo tau indirectly by clearing plaques.
"This is certainly a provocative study. It's tightening the link between amyloid and tau," says neuroscientist John Trojanowski of the University of Pennsylvania, Philadelphia. In addition to prompting the development of vaccines that work early in disease--before tangles form--the results should stimulate scientists to find ways of eliminating these recalcitrant structures once they've encamped, he adds, although such treatments would be useful only if investigators also develop ways to identify people in the early stages of AD. If these findings translate to humans, perhaps researchers will rely on -amyloid antibodies to bar plaques and tangles--like a marshal who keeps his city outlaw free.
August 11, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150